Myotonic dystrophy (DM) is one of many diseases under the umbrella of muscular dystrophy. DM is the most common form of adult onset muscular dystrophy, affecting 1 in 8000 people (Ranum & Day, Am. J. Hum. Genet. 74:793-804, 2004). DM is caused by an expansion of three or four nucleotide repeats: a CUG expansion in subjects with myotonic dystrophy type I (DM1), and a CCUG expansion in subjects with myotonic dystrophy type 2 (DM2). DM1 is responsible for the majority of subjects with myotonic dystrophy, while DM2 is relatively rare. In DM1, CUG repeats are found in the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19 (Aslanidis et al., Nature 355:548-551, 1992; Brook et al., Cell 68:799-808, 1992). In DM2, the CCUG repeats are found in the zinc finger 9 (ZNF9) gene, a gene on chromosome 3 encoding a zinc finger protein (Liguori et al., Science 293:864-867, 2001). For both DM1 and DM2 the repeats are found in non-translated regions of the pre-mRNA. In DM1 the expanded CUG triplet repeats are in the 3′ untranslated region (UTR), unless alternative splicing occurs within this region of the DMPK transcript, in which case, the CUG repeats are within the last intron before the last exon (Tiscornia & Mahadevan, Mol. Cell. 5:959-967, 2000). The CCUG repeats in ZNF9 are within the first intron (Liguori et al., 2001).
Both DM1 and DM2 subjects display many of the same symptoms (myotonia, progressive muscle weakness and wasting, cataracts, and cardiac and developmental defects), strongly suggesting that both DM1 and DM2 work through the same or very similar mechanisms (Tapscott & Thornton, Science 293:816-817, 2001). The current model is that an RNA gain-of-function mechanism is responsible for causing DM, meaning that expansion of the CUG or CCUG repeats results in an RNA molecule that has a new function, apparently overriding other cellular pathways.
In the case of DM1, the normal length of the CUG triplet repeats in DMPK is in the range of 5-37 repeats, the “pre-mutation” range of repeats is 50-180, and the disease causing range is from 200 to greater than 2000 repeats (Ranum & Day, 2004). In the case of DM2, normal alleles have 11-26 CCUG tetranucleotide repeats, while pathogenic alleles have from 75 to more than 11,000 repeats. For DMPK, biochemical studies have shown that with just 11 CUG repeats, a stable triplet repeat stem-loop structure is able to form, and as the number of repeats increases so does the length and stability of the stem-loop (Napierala & Krzyzosiak, J. Biol. Chem. 272:31079-31085, 1997). The number of repeats and possibly the length of the stem correlate with the severity of DM; the larger the number of repeats, the more severe the symptoms of DM displayed by the subject (Ranum & Day, 2004).